LRRK2 inhibitors induce reversible changes in nonhuman primate lungs without measurable pulmonary deficits

2020 ◽  
Vol 12 (540) ◽  
pp. eaav0820 ◽  
Author(s):  
Marco A. S. Baptista ◽  
Kalpana Merchant ◽  
Ted Barrett ◽  
Sakshi Bhargava ◽  
Dianne K. Bryce ◽  
...  
Keyword(s):  
Lung Function ◽  
Nonhuman Primates ◽  
Drug Withdrawal ◽  
Positive Control ◽  
Repeat Dose ◽  
Type Ii ◽  
Histological Changes ◽  
Once Daily ◽  
Toxicology Study ◽  
Activating Mutation

The kinase-activating mutation G2019S in leucine-rich repeat kinase 2 (LRRK2) is one of the most common genetic causes of Parkinson’s disease (PD) and has spurred development of LRRK2 inhibitors. Preclinical studies have raised concerns about the safety of LRRK2 inhibitors due to histopathological changes in the lungs of nonhuman primates treated with two of these compounds. Here, we investigated whether these lung effects represented on-target pharmacology and whether they were reversible after drug withdrawal in macaques. We also examined whether treatment was associated with pulmonary function deficits. We conducted a 2-week repeat-dose toxicology study in macaques comparing three different LRRK2 inhibitors: GNE-7915 (30 mg/kg, twice daily as a positive control), MLi-2 (15 and 50 mg/kg, once daily), and PFE-360 (3 and 6 mg/kg, once daily). Subsets of animals dosed with GNE-7915 or MLi-2 were evaluated 2 weeks after drug withdrawal for lung function. All compounds induced mild cytoplasmic vacuolation of type II lung pneumocytes without signs of lung degeneration, implicating on-target pharmacology. At low doses of PFE-360 or MLi-2, there was ~50 or 100% LRRK2 inhibition in brain tissue, respectively, but histopathological lung changes were either absent or minimal. The lung effect was reversible after dosing ceased. Lung function tests demonstrated that the histological changes in lung tissue induced by MLi-2 and GNE-7915 did not result in pulmonary deficits. Our results suggest that the observed lung effects in nonhuman primates in response to LRRK2 inhibitors should not preclude clinical testing of these compounds for PD.

scholarly journals In-Vivo Effectiveness of 5% Azadirachta indica Oil Cream as Anti-Scabies

2019 ◽  
Vol 4 (1) ◽  
pp. 10
Author(s):  
Patihul Husni ◽  
Mayang K. Dewi ◽  
Norisca A. Putriana ◽  
Rini Hendriani
Keyword(s):  
Azadirachta Indica ◽  
Recovery Time ◽  
Sarcoptes Scabiei ◽  
Positive Control ◽  
Negative Control ◽  
Neem Oil ◽  
Once Daily ◽  
Irritation Test ◽  
Primary Irritation

Scabies is an infectious skin disease caused by mite Sarcoptes scabiei. Neem tree (Azadirachta indica) has the potential to be used as an anti-parasite due to the presence of azadirachtin compound that is commonly found in the seeds. The aim of this study was to evaluate in-vivo effectiveness of neem oil as an anti-scabies. This study used an experimental method.  The effectiveness of the cream as an anti-scabies was tested on New Zealand white rabbits which were infected with scabies. Permethrin cream was used as a positive control and cream base was used as a negative control.  Cream was applied once daily and left for 8 hours. The data were analyzed using Kruskal Wallis and Mann Whitney. Dermal acute irritation test was performed by applying  0.5 g cream on the rabbit dorsal. We found that 5% neem oil cream was effective as an anti-scabies with 20-21 days recovery time. The recovery time is longer than permethrin cream (7-8 days), but shorter compared to negative control with recovery time over 30 days. Primary irritation index for 5% neem oil creams was 0, indicating negligible irritation category. In conclusion, A. indica cream was effective for the treatment of scabies although its recovery time is shorter than permethrin cream.  Keywords: effectiveness test, irritation test, neem oil cream, scabies

scholarly journals MORPHOLOGICAL AND HISTOLOGICAL EFFECTS OF BRUCEINE A ON THE LARVAE OF AEDES AEGYPTI LINNAEUS (DIPTERA: CULICIDAE)

2018 ◽  
Vol 11 (10) ◽  
pp. 422
Author(s):  
Dwi Sutiningsih ◽  
Mustofa Mustofa ◽  
Tri Baskoro Tunggul Satoto ◽  
Edhi Martono
Keyword(s):  
Epithelial Cells ◽  
Aedes Aegypti ◽  
Histological Change ◽  
Negative Control Group ◽  
Positive Control ◽  
Negative Control ◽  
Control Group ◽  
Histological Changes ◽  
Brucea Javanica ◽  
Gastrointestinal Damage

Objective: This study aimed to determine a target of action of bruceine A on the basis of its morphological and histological effects on the larvae of Aedes aegypti Linnaeus.Methods: Bruceine A was isolated from Brucea javanica (L.) Merr. seeds in accordance with the Mangungsong method. Larvae of A. Aegypti (L.) in instar III to the beginning of instar IV were treated with various concentrations of bruceine A. The negative control group did not receive any treatment, whereas the positive control group received 1 ppm temefos. Dead larvae were collected after 24 h of treatment for the examination of morphological and histological changes.Results: The negative control group did not exhibit any morphological and histological changes. Larvae treated with bruceine A, however, had visible damaged heads, cuticles, digestive and respiration tracts, respiratory siphons, and setae, and they were smaller than normal larvae. Larvae treated with temefos exhibited gastrointestinal damage, narrowed breathing tubes, cuticle damage, and detached/damaged seta feathers. The necrosis of gastrointestinal epithelial cells was the major histological change exhibited by larvae treated with various concentrations of bruceine A or 1 ppm temefos.Conclusion: The targets of action of bruceine A in A. aegypti (L.) larvae are the head/caput, cuticle, setae, siphon, and gastrointestinal and respiratory tracts.

scholarly journals Formoterol Thrice Weekly Does Not Result in the Development of Tolerance to Bronchoprotection

2003 ◽  
Vol 10 (1) ◽  
pp. 23-26 ◽  
Author(s):  
Beth E Davis ◽  
John K Reid ◽  
Donald W Cockcroft
Keyword(s):  
Crossover Trial ◽  
Positive Control ◽  
Forced Expiratory Volume ◽  
Weekly Administration ◽  
Double Blind ◽  
Once Daily ◽  
Regular Treatment ◽  
Significant Difference ◽  
Direct Acting ◽  
Development Of Tolerance

BACKGROUND: Loss of bronchoprotection routinely follows regular treatment with beta2-agonists. There are no data on the effects on bronchoprotection for thrice weekly use of a beta2-agonist.METHODS: A double-blind, randomized, placebo controlled crossover trial was conducted to investigate the effects of thrice weekly administration of 12 μg of formoterol versus placebo on bronchoprotection against methacholine. As an expected positive control, formoterol 12 μg once daily was also evaluated.RESULTS: There was no significant difference versus placebo in the bronchoprotective effects of 12 μg of formoterol administered on day 8, following daily treatment for seven days or treatment every other day (analysis of variance P=0.34). However, a nonsignificant trend towards lower concentration of methacholine that caused a 20% fall in forced expiratory volume in 1 s developed only following the daily formoterol dosing.CONCLUSIONS: Thrice weekly dosing does not result in the development of tolerance to bronchoprotection against the direct acting stimulus methacholine.

scholarly journals Lung function, pharmacokinetics, and tolerability of inhaled indacaterol maleate and acetate in asthma patients

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
David Miller ◽  
Soniya Vaidya ◽  
Juergen Jauernig ◽  
Brian Ethell ◽  
Kristina Wagner ◽  
...  
Keyword(s):  
Lung Function ◽  
Systemic Exposure ◽  
Forced Expiratory Volume ◽  
Fixed Dose ◽  
Chronic Obstructive ◽  
Electronic Diary ◽  
Double Blind ◽  
Once Daily ◽  
Long Acting ◽  
Salt Forms

Abstract Background Indacaterol maleate delivered with the Breezhaler® inhalation device is a long-acting β2-agonist approved for chronic obstructive pulmonary disease. In the development of a once daily, inhaled fixed dose combination (FDC) of indacaterol, glycopyrronium bromide (a long-acting muscarinic antagonist), and mometasone furoate (an inhaled corticosteroid [ICS]) for the treatment of patients with asthma, the acetate salt of indacaterol is used instead of the maleate salt. Here, we investigated the lung function, pharmacokinetics (PK) and safety of indacaterol maleate 150 μg once daily (o.d.) and indacaterol acetate 150 μg o.d. in comparison with placebo. Methods This was a randomised, double-blind, three-period crossover study (ClinicalTrials.gov identifier, NCT03257995) in patients with asthma on background ICS therapy. Patients with percent predicted pre-bronchodilator forced expiratory volume per second (FEV1) ≥50% and ≤ 90% were included in the study. Patients received indacaterol maleate 150 μg o.d., indacaterol acetate 150 μg o.d., or placebo on top of stable background ICS in randomised sequence. Trough FEV1 was assessed after 14 days of treatment. PK of indacaterol salts were assessed at steady state after 14 days of treatment; peak expiratory flow (PEF) rate and rescue medication use were collected with a combined PEF-meter/electronic diary throughout the study. Results Of the 54 adult patients (median age of 48 years), 51 patients completed the study. Both indacaterol salts demonstrated statistically significant improvements in trough FEV1 of 186 mL (maleate) and 146 mL (acetate) compared with placebo (both P < 0.001). FEV1 AUC0-4h improved by 248 mL (maleate) and 245 mL (acetate), and PEF by 33 L/min (maleate) and 30.8 L/min (acetate) versus placebo. Systemic exposure of indacaterol (AUC0-24h,ss and Cmax,ss on Day 14) was comparable after administration of both salt forms. Both salt forms demonstrated a good safety profile and were well tolerated, with a difference in the reporting frequency of AEs of coughing (maleate, 23.5%; acetate, 0%). Conclusions In patients with asthma, indacaterol maleate and acetate elicited comparable and significant improvements in lung function compared with placebo and achieved comparable systemic exposure. Both indacaterol salts were safe and well tolerated. Trial registration ClinicalTrials.gov NCT03257995 June 06, 2017

Aging impairs alveolar epithelial type II cell function in acute lung injury

2020 ◽  
Vol 319 (5) ◽  
pp. L755-L769 ◽  
Author(s):  
Tolga Yazicioglu ◽  
Christian Mühlfeld ◽  
Chiara Autilio ◽  
Cheng-Kai Huang ◽  
Christian Bär ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Function ◽  
Lung Injury ◽  
Cell Senescence ◽  
Proliferation Rate ◽  
Type Ii ◽  
Alveolar Epithelial ◽  
Surfactant Activity ◽  
Old Mice ◽  
Young Mice

Morbidity and mortality rates in acute lung injury (ALI) increase with age. As alveolar epithelial type II cells (AE2) are crucial for lung function and repair, we hypothesized that aging promotes senescence in AE2 and contributes to the severity and impaired regeneration in ALI. ALI was induced with 2.5 μg lipopolysaccharide/g body weight in young (3 mo) and old (18 mo) mice that were euthanized 24 h, 72 h, and 10 days later. Lung function, pulmonary surfactant activity, stereology, cell senescence, and single-cell RNA sequencing analyses were performed to investigate AE2 function in aging and ALI. In old mice, surfactant activity was severely impaired. A 60% mortality rate and lung function decline were observed in old, but not in young, mice with ALI. AE2 of young mice adapted to injury by increasing intracellular surfactant volume and proliferation rate. In old mice, however, this adaptive response was compromised, and AE2 of old mice showed signs of cell senescence, increased inflammatory signaling, and impaired surfactant metabolism in ALI. These findings provide evidence that ALI promotes a limited proliferation rate, increased inflammatory response, and surfactant dysfunction in old, but not in young, mice, supporting an impaired regenerative capacity and reduced survival rate in ALI with advancing age.

Influence of phosphatidylglycerol on the uptake of liposomes by alveolar cells and on lung function

2005 ◽  
Vol 98 (5) ◽  
pp. 1784-1791 ◽  
Author(s):  
D. L. H. Poelma ◽  
B. Lachmann ◽  
J. J. Haitsma ◽  
L. J. Zimmermann ◽  
J. F. van Iwaarden
Keyword(s):  
Lung Function ◽  
Alveolar Macrophages ◽  
Alveolar Type ◽  
Type Ii Cells ◽  
Type Ii ◽  
Negative Effects ◽  
Alveolar Cells ◽  
Alveolar Type Ii Cells ◽  
High Concentrations

The effect of phosphatidylglycerol on the uptake of surfactant-like liposomes by alveolar type II cells and alveolar macrophages as well as the effect on endogenous surfactant function was studied in vivo. Healthy ventilated rats were intratracheally instilled with fluorescent labeled liposomes with different concentrations of phosphatidylglycerol. Lung function was determined by monitoring arterial oxygenation and, at the end of the experiment, by recording static pressure-volume curves. In addition, alveolar cells were isolated, and cell-associated fluorescence was determined using flow cytometry. The results show that, in the presence of cofactors (Ca2+, Mg2+), phosphatidylglycerol stimulates the uptake by alveolar macrophages but hardly affects the uptake by alveolar type II cells. High concentrations of phosphatidylglycerol reduce the number of alveolar macrophages in the alveolar space and deteriorate lung function. On the other hand, the presence of cofactors protects the lung against the negative effects of phosphatidylglycerol on endogenous surfactant and alveolar macrophages. This study indicates that the phosphatidylglycerol concentration may play a fundamental role in the surfactant function and metabolism depending on the presence of so-called cofactors like calcium and magnesium; further study is needed to clarify the mechanisms involved.

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